Discriminating Protective from Nonprotective Plasmodium-Specific CD8+ T Cell Responses

Abstract

Despite decades of research, malaria remains a global health crisis. Current subunit vaccine approaches do not provide efficient long-term, sterilizing immunity against Plasmodium infections in humans. Conversely, whole parasite vaccinations with their larger array of target antigens have conferred long lasting sterilizing protection to humans. Similar studies in rodent models of malaria reveal that CD8+ T cells play a critical role in liver-stage immunity after whole parasite vaccination. However, it is unknown whether all CD8+ T cell specificities elicited by whole parasite vaccination contribute to protection, an issue of great relevance for enhanced subunit vaccination. Here we show that robust CD8+ T cell responses of similar phenotype are mounted following prime-boost immunization against Plasmodium berghei GAP5041-48, S20318-325, TRAP130-138 or CSP252-260 protein-derived epitopes in mice, but only CSP252-260- and TRAP130-138-specific CD8+ T cells provide sterilizing immunity and reduce liver parasite burden following sporozoite challenge. Further, CD8+ T cells specific to sporozoite surface-expressed CSP and TRAP proteins, but not the intracellular GAP50 and S20 proteins, are efficiently recognized by sporozoite-infected hepatocytes in vitro. These results suggest that 1) protection-relevant antigenic targets, regardless of their immunogenic potential, must be efficiently presented by infected hepatocytes for CD8+ T cells to eliminate liver-stage Plasmodium infection and 2) proteins expressed on the surface of sporozoites may be good target antigens for protective CD8+ T cells.

Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity

“…These data suggested the intriguing hypothesis that expansion of the circulating T em population induced by IAV infection could increase numbers of lung T rm . To test this hypothesis, we exposed PR8-GP33 immune or naive P14 recipient mice to systemic infection with recombinant L. monocytogenes expressing GP33 (LM-GP33) or an unrelated epitope derived from the P. berghei TRAP protein (LM-TRAP) (32, 33) 45 days after the initial PR8-GP33 infection (Fig. 8a).…”

“…LCMV Armstrong infections were performed by intraperitoneal (IP) injection of 2×10 5 PFU of the virus. Systemic booster/mock booster immunizations were performed by IV injection of 10 7 CFU of recombinant L. monocytogenes expressing GP33 (LM-GP33) or a P. berghei TRAP-derived epitope (LM-TRAP (32). …”

γδ T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations

“…In the absence of γδ T cells during vaccination, there was diminished activation of CD8 T cells in the periphery and reduced numbers of PbTRAP 130 specific CD8 T cells in the liver and the spleen that are required for sterile immunity (38). Since we did not specifically stain for markers of tissue resident T cells, we cannot exclude the possibility that some of these responses are due to circulating effector memory T cells.…”

A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene

“…GAP50 40–48 -specific memory CD8 + T cells are not protective during the liver-stage of murine malaria (Doll et al, 2016; Horne-Debets et al, 2016; van der Heyde et al, 1993; Vinetz et al, 1990), and the capacity of CD8 + T cells to protect during blood-stage malaria remains controversial (Horne-Debets et al, 2016; Imai et al, 2010; van der Heyde et al, 1993; Vinetz et al, 1990). Thus, the pathogenic effects of GAP50 40–48 -specific CD8 + T cells in ECM most likely resulted from a large population of precursors, which expanded rapidly after infection to generate substantial numbers of effector cells, leading to sustained immune activation without elimination of the pathogen.…”

“…All restimulations were performed in triplicate. IFNγ-producing CD8 + T cells were identified using a standard intracellular cytokine staining protocol (Doll et al, 2016). Data are expressed relative to the percentage of CD8 + T cells producing IFNγ in response to the wt peptide.…”